The goals of the Oral Cancer Research Program (OCRPP) at The Ohio State University are to: 1) enhance and facilitate investigations of those interactions between human cells of the oral cavity and tobacco by- products that lead to adverse biological responses; 2) coordinate activities that will utilize the information obtained from these interactions, at malignant oral lesions; and, 3) promote and develop research that will determine the efficacy of control and intervention strategies. Established investigators in the Oral Cancer Research Program Project "Molecular Events in the Progress/Prevention of Oral Cancer" are concentrating their efforts in five major areas of research (Research Projects) to address this central theme. Research Project 1 (Carcinogen/Oxidant Synergism in Oral Cancer Initiation is focussing on initiating events in oral cancer. They will determine the metabolic fate of tobacco-associated carcinogens (TAC) in oral mucosal cells and how the metabolism of these compounds may be modified by ethanol. Project 1 will also explore the ability of oral mucosal cells to respond to physiologically relevant concentrations of reactive oxygen species. The genetic events leading to the establishment of premalignant and malignant lesions will be studied by Research Projects 2 and 3. Research Project 2 (Role of G/1 Phase Regulatory Genes and Identification of Differentially Expressed Novel Genes in Premalignant Oral Lesions) will evaluate those genes more closely associated with aberrant cell proliferation. Research Project 3 (Inactivation of the TGF-beta Receptor Complex in Oral Cancer Development) will study the loss of control of cell cycle proliferation by evaluating the effect of gene alterations (mutations, deletions, methylation) on the TGF-beta receptor complex (i.e., protein binding, kinase activity, and modification of specific downstream substrates). Research Project 4 (Molecular Mechanisms in Conversion of Cells in Oral Tissues from Normal to Premalignant and from Premalignant to Malignant) will explore those conditions involved in the transformation of normal cells into premalignant cells by TACs and the conversion of premalignant oral dysplasias into squamous cell carcinomas. In concert with Research Projects 2 and 3, the cells transformed in vitro by TAC, or concerted to malignancy by TAC, will be examined to determine if the same changes occur in cell cycle regulatory genes and the TGFbeta receptor complex as are found in premalignant and malignant tissues form patients. The rationale for the studies in Research Projects 1, 2, 3, and 4 is to provide information on those premalignant to the malignant stage. This information will be employed by Research Project 3 (Chemoprevention of Premalignant and Malignant Oral Tumors) which will develop strategies for intervention and preventive measures whereby the cytotoxic or genetic damage manifested by tobacco-related products is inhibited or modified and progression of dysplastic lesions to malignancy is prevented. This involves both natural and synthetic chemicals that affect the activation and detoxification of TAC and that interact with and modify the function of critical cellular genes or gene products that are responsible for the generation and maintenance of premalignant dysplasias and the conversion of these dysplasia into malignant oral cancers. In summary, the major thrust of the Program Project is to investigate the multiple genetic pathways in the loss of regulatory control of cell proliferation, differentiation, and apoptosis. With this information, we should be able to determine which chemopreventative agents will best intervene in the early stages of the cascade of events leading to oral cancer and by understanding the nature of the molecular changes occurring in the early stages of disease, we can develop strategies directed towards the modulation of those events that are specifically involved in the process.